Natural killer (NK) cells have been recently implicated as critical modulators of adaptive immunity. In particular, NK cell interactions with dendritic cels (DCs) are central to shaping effective anti-cancer immune responses, holding great implications for DC- and other cell-based cancer immunotherapies. We have previously demonstrated that, in contrast to IL-2-activated 'killer' NK cells capable of eliminating immune-stimulatory DCs, IL-18-activated 'helper' NK cells can potentiate anti-tumor immune responses through DC activation and the enhancement of DC-induced type-1 immunity. However, our new preliminary data indicate that such IL-18- activated NK cells may also have undesirable immune-suppressive functions through the hyper-activation of myeloid-derived suppressor cells (MDSCs), reinforced by autocrine COX2-PGE2 feedback in MDSCs. This further suggests the possibility of COX2-PGE2 axis inhibition in reversing the NK-mediated up-regulation of MDSC functions, while preserving or enhancing NK-mediated DC activation. In this proposal, using IL-2- and IL-18-activated NK cells as a model, I seek to identify the mechanisms by which 'killer' and 'helper' NK cells differentially acquire and perform desirable immune-stimulatory (tumor- killing, MDSC-killing, and DC-activating) and undesirable immune-suppressive (DC-killing and MDSC- activating) functions. This mechanistic knowledge will be subsequently used to examine potential pharmacologic or biologic methods of modifying NK cell interactions with DCs and MDSCs to maximize desirable anti-cancer immune responses. Overall, this project will provide new functional and mechanistic insights into the acquisition and performance of NK cell immune-stimulatory and immune-suppressive interactions with DCs and MDSCs, and will identify targets for the therapeutic separation of these desirable and undesirable NK cell activities for the improvement of cancer immunotherapy. PUBLIC HEALTH RELEVANCE: Cancer remains the leading cause of death under age 85 in the US, highlighting the need for innovative approaches to cancer treatment, including strategies to enhance the effectiveness of immune responses against cancer. Using highly-relevant human tumor models and clinical cancer materials, this proposal seeks to define the key interactions between three cell types critical to the immune response and immune evasion of cancer: natural killer (NK) cells, dendritic cells, and myeloid-derived suppressor cells. The results of this study will directly contribute to the improvement of cell-based cancer therapies by informing strategies for the selective enhancement of immune-stimulatory anti-cancer NK cell activities.